Cell type and cortex-specific RNA editing in single human neurons informs neuropsychiatric disorders

Conversion of adenosine to inosine in RNA by ADAR enzymes occurs at thousands of sites in the human transcriptome, and is essential for healthy brain development. This process, known as 9RNA editing9, is dysregulated in many neuropsychiatric diseases, but is little understood at the level of individual neurons. We examined full-length nuclear transcriptomes of 3,055 neurons from six cortical regions of a neurotypical post-mortem female donor and identified 40,861 high-confidence edited sites. The majority of sites were located within Alu repeats in introns or 39 UTRs, and were present in previously published RNA editing databases. We identified 15,784 putative novel RNA editing sites, 30% of which were also detectable in independently generated neuronal transcriptomes from unrelated donors. The strongest correlates of global editing rates were expression levels of small nucleolar RNAs from the SNORD115 and SNORD116 cluster (15q11), known to modulate serotonin receptor processing and to colocalize with ADAR2, one of three known RNA editing enzymes in humans. As expected, expression of DNA and RNA binding proteins were negatively associated with editing. We present evidence for dysregulated RNA editing in six rare genetic conditions; and report 117 differentially edited sites between cortical regions and neuronal subtypes. These results provide spatial and neurophenotypic context for 1,871 and 998 sites that are differentially edited in the brains of schizophrenic and autistic patients respectively, and a reference for future studies of RNA editing in single brain cells from these cohorts.